https://orcid.org/0000-0003-1141-4471
Figures & data
Figure 1. Overview of the production and absorption sites, and transport of acetate, propionate and butyrate (SCFAs)
(A) Most undigested carbohydrates are fermented in the cecum and ascending colon, whereas the SCFA absorption takes place along the whole colon. A negative correlation between the SCFA concentrations and pH exists. The highest SCFA concentration levels are in the cecum and ascending colon, where the pH is approximately 5.6, whereas in the sigmoid and rectum, the pH is higher (approximately 6.6) and the SCFA concentrations are lower. (B) In the colon, acetate, propionate, and butyrate are found in an approximate molar ratio of 3:1:1, respectively. Most SCFAs are utilized by colonocytes as an energy source. The SCFAs that are not used by these cells can be transported toward the hepatic portal vein, where the SCFA concentrations are 375 µmol/l, and the hepatic vein, where the SCFA concentrations are 39% of those found in portal blood. MR, molar ratio. SCFAs, short-chain fatty acids. Created with BioRender.com
Figure 2. SCFA biosynthesis pathways from the dietary carbohydrate fermentation and the major SCFA-producing bacteria for each pathway
Acetate can be formed by the Wood-Ljungdahl pathway and from pyruvate via acetyl-CoA. Acetyl-CoA can be also produced from lactate by lactate-utilizing bacteria. Three pathways exist for the propionate formation, namely acrylate, succinate, and propanediol pathways. The two first use PEP and the latter utilizes deoxy sugars such as rhamnose and fucose. Butyrate can be formed through the classical pathway from the condensation of two acetyl-CoA molecules or by the butyryl-CoA: acetate CoA-transferase route, in which butyryl-CoA is converted into butyrate and acetyl-CoA using exogenously derived acetate. DHAP, dihydroxyacetone phosphate; PEP, phosphoenolpyruvate. Created with BioRender.com
Figure 3. Beneficial roles of SCFA in cardio-metabolic health and the indirect mechanisms involved
(A) Undigested carbohydrates reach the intestine, where they are fermented by the SCFA-producing bacteria generating acetate, propionate, and butyrate. SCFAs can act using two different mechanisms: 1) direct action on the enterocytes, maintaining the gut barrier integrity or 2) indirect action regulating the inflammatory and immune response, blood pressure, energy intake and use, and lipid and glucose homeostasis, through the mechanisms illustrated in (B). (B) 1) Inhibition of K/HDAC leads to histone hyperacetylation, which turns in a higher accessibility of transcription factors to the promoter regions of different genes; 2) signaling transduction activation (in the small intestine, colon, liver, spleen, heart, skeletal muscle, neurons, immune cells, and adipose tissues), and GLP-1 and PYY secretion (in intestinal enteroendocrine L-cells) caused by the binding of SCFAs to the G protein-coupled receptors, and increase of cAMP levels by the binding of propionate or acetate to the receptor Olfr78/OR51E2 (in vascular smooth muscle cells in the peripheral vasculature and renal afferent arteriole). GLP-1 and PYY enter into the systematic circulation exerting benefits in different tissues and cells; 3) butyrate working as a ligand of the AHR and PPARγ, leading to the expression of genes dependent on these two transcription factors. AMPK, AMP-activated protein kinase; AHR, aryl hydrocarbon receptor; BP, blood pressure; cAMP, cyclic adenosine monophosphate; FFAR, free fatty acid receptor; GLP-1, glucagon-like peptide-1; GPR109a, G-protein coupled receptor-109a; IL, interleukins; K/HDAC, lysine/histone deacetylase; LPS, lipopolysaccharides; NF-κB, nuclear factor kappa β; Olfr78, olfactory receptor-78; PYY: peptide YY; SCFA, short-chain fatty acid; TF, transcription factor. Created with BioRender.com
Table 1. Summary of studies reporting beneficial effects of SCFAs in cardio-metabolic health through different traits
Table 2. Studies reporting the modulation by diets of SCFA-producing bacteria, SCFA levels, and risk factors associated with cardio-metabolic health